The proposal is to continue analysis of feline retroviruses that induce AIDS-like syndromes in cats. Over the past decade the project made contributions to the understanding of retrovirus-induced AIDS-like disease in cats and provided conceptual lead information to the study of HIV. The plan is to complete a transition from analysis of disease processes induced by the oncovirus FeLV to those caused by the lentivirus FIV focusing on answering questions important to the current study of HIV. Of great import to the ability to control HIV infection has been the recent recognition that: 1) plasma virus load is an important predictor of progression; 2) early events in infection substantially influence disease course, and; 3) new antiviral drugs and combinations can greatly reduce virus load for sustained periods. A logical hypothesis to consider is that by diminishing virus load early on in the plasma and its source tissues, we may drive the hypothetical "set point" of virus lower and delay or stop disease progression. Potent antiviral regimens are now being evaluated in HIV-infected volunteers, lacking, however, is a rapid model for the evaluation of the impact of sustained as well as intermittent therapies to determine when therapies are likely to have superior downstream benefits. The feline/FIV model provides a facile infection model, and with the recent description of a highly pathogenic strain of FIV, a facile disease model. The proposal is to use this model to determine whether combination antiviral therapy will allow the host to resist eventual disease. These studies will be conducted with a newly characterized FIV strain that causes fatal immunodeficiency disease in >60% of cats in the first 6 months. It is proposed to test hypotheses that: 1) plasma virus is derived predominantly from thymus and lymph nodes and that effective therapies must greatly suppress viral replication in these sites; 2) early therapy will diminish virus replication in all tissue reservoirs and extend survival (from about 25% to 100% at 12 mo) except in animals in which multiple drug resistant viruses emerge; 3) reducing viral load with short term therapy early in infection will prolong the asymptomatic period and reduce the likelihood that antiviral resistance will emerge, and; 4) FIV can be modified to be susceptible to HIV-1 PR inhibitors for evaluation in the feline/FIV model.